KR101150504B1 - Novel crystal forms of irinotecan hydrochloride - Google Patents

Abstract

The present invention provides novel crystalline forms of irinotecan hydrochloride and methods for their preparation, pharmaceutical compositions containing these new crystalline forms and methods for treating metastatic carcinoma of the colon or rectum.

Description

Novel crystalline form of irinotecan hydrochloride {NOVEL CRYSTAL FORMS OF IRINOTECAN HYDROCHLORIDE}

Related application

This application claims priority based on US Provisional Patent Application No. 60 / 718,827, filed September 20, 2005. All contents of US Provisional Patent Application No. 60 / 718,827 are incorporated herein by reference.

Technical field

The present invention relates to 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin monohydrochloride trihydrate (irinotecan hydrochloride). More specifically, the newly discovered crystalline forms, methods for preparing these new crystalline forms, pharmaceutical compositions containing these new crystalline forms, and colons using these new crystalline forms compared to previously produced irinotecan hydrochloride, It relates to the treatment of metastatic carcinoma of the rectum.

Molecular structural formula

Irinotecan  Hydrochloride

HCl

3H₂O이며, 분자량이 677.19인 7-에틸-10-[4-(1-피페리디노)-1-피페리디노] 카르보닐옥시캄토테신 일염산염 삼수화물은 국소 이성화 효소 Ⅰ 억제제류의 항종양제이다. 이리노테칸 염산염은 캄토테신의 반합성 유도체이고, 캄프토데카 아쿠미나타(Camptotheca acuminata) 등의 식물로부터 추출된 알칼로이드 추출물이다. 식약청 (FDA)은 5-플루오로우라실 및 류코보린과 결합한 이리노테칸 염산염을 결장 또는 직장의 전이 암종 환자용 제1선 치료 성분으로서 승인하였다. 식약청은 이리노테칸 염산염을 초기 플루오로우라실계 치료에 이어 재발 또는 진행된 결장 또는 직장의 전이 암종 환자 치료용으로도 역시 승인하였다 (Physician's Desk Reference, 59th ed., 2005). 이리노테칸 염산염은 주사제로서 캄프토사르^®(Camptosar^®)라는 상품명으로 시판되고 있다.And the general diet of C ₃₃ H ₃₈ N ₄ O ₆

HCl

7-Ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin monohydrochloride trihydrate with 3H ₂ O and a molecular weight of 677.19 is an anti-isomerization agent of topical isomerase I inhibitors. It is a neoplastic agent. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin and is an alkaloid extract extracted from plants such as Camptotheca acuminata . The Food and Drug Administration (FDA) approved irinotecan hydrochloride in combination with 5-fluorouracil and leucovorin as the first-line therapeutic ingredient for patients with metastatic carcinoma of the colon or rectum. The FDA also approved irinotecan hydrochloride for the treatment of patients with metastatic carcinoma of the colon or rectum following initial fluorouracil treatment ( Physician's Desk Reference , 59th ed., 2005). Irinotecan hydrochloride as an injection has been sold under the trade name of Kam neoplasm? Sar ^® (Camptosar ^®).

The present invention relates to a novel solid state crystalline form of irinotecan hydrochloride.

U.S. Patent No. 4,604,463 discloses various preparations of spherical irinotecan and irinotecan hydrochloride. The '463 patent is incorporated by reference in its entirety, and in detail is incorporated herein by reference to the description of the synthesis of irinotecan and irinotecan hydrochloride from commercially accessible starting materials.

 In Example 19 of the '463 patent, 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin is 10-chlorocarbonyl in dry dioxane. Prepared by suspending oxy-7-ethylcamptothecin. 4-piperidinopiperidine was added to this suspension. The mixture was stirred until the starting material was consumed. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue was separated and purified using silica gel column chromatography to obtain 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy Camptothecin was obtained.

Example 28 of the '463 patent, wherein 7-ethyl-10 is dissolved by dissolving 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine in anhydrous piperidine. -[4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin was prepared and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in CHCl ₃ . The solution was washed successively with 7% aqueous NaHCO ₃ , saturated aqueous NaCl solution, and the CHCl ₃ layer was dried using MgSO ₄ , filtered and evaporated in vacuo. The residue was passed through a short silica gel column to decolorize to obtain 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin as a pale yellow substance, which was recrystallized from ethanol. To give colorless needles.

In Example 37 of the '463 patent, 1/10 N in a cooling suspension of 7-ethyl-10- [1- (4-piperidino) piperidino] carbonyloxycamptothecin suspended in distilled water. 7-Ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin hydrochloride was prepared by adding HCl. The suspension was stirred vigorously for 5 minutes while cooling in an ice bath. The solution was passed through a filter (0.22 μm, SLGS 025 OS) and the filtrate was lyophilized overnight to give 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin Hydrochloride was obtained as a pale yellow amorphous solid.

The inventors have discovered and described a novel crystalline form of irinotecan hydrochloride that is easier to handle during the manufacturing process than conventional irinotecan hydrochloride.

There is a need for new crystalline forms of irinotecan. The discovery of new crystalline forms of pharmaceutical compounds provides for improved processing and preparation of pharmaceutical products containing irinotecan hydrochloride. The new crystalline forms increase the possibilities available to scientists involved in the manufacture of pharmaceutical products, thereby producing new and improved pharmaceutical compositions that cannot be obtained by other methods, except for the present invention of the new crystalline forms. To make it possible.

Summary of the Invention

A first aspect of the invention relates to crystalline Form I of irinotecan hydrochloride. Type I can be confirmed by the X-ray diffraction pattern. Irinotecan hydrochloride Form I can be prepared under controlled conditions using ethanol, N-heptane and hydrochloric acid solvent.

A second aspect of the present invention relates to crystalline Form II of irinotecan hydrochloride. Type II can be confirmed by the X-ray diffraction pattern. Irinotecan hydrochloride Form II can be prepared under controlled conditions using ethanol and hydrochloric acid solvent.

A third aspect of the present invention relates to crystalline Form III of irinotecan hydrochloride. Type III can be confirmed by the X-ray diffraction pattern. Irinotecan hydrochloride Form III can be prepared under controlled conditions using methanol, ethyl acetate and hydrochloric acid solvent.

A fourth aspect of the present invention relates to Form IV of irinotecan hydrochloride. Type IV can be confirmed by the X-ray diffraction pattern. Irinotecan hydrochloride Form IV can be prepared under controlled conditions using ethanol, ethyl acetate and hydrochloric acid solvent.

The present invention provides a crystalline form of irinotecan hydrochloride that is more easily filtered out of solution compared to conventional irinotecan hydrochloride. Increased ease of filtration is useful because it facilitates handling and processing of irinotecan hydrochloride during the manufacturing process.

Other objects and features of the present invention will become apparent upon consideration of the following detailed description taken in conjunction with the accompanying drawings. However, it is to be understood that these drawings are not intended to limit the invention, but are intended for purposes of explanation only, which should be referred to for the appended claims. In addition, it is to be understood that the drawings are not necessarily drawn to be limiting and the drawings are intended to conceptually describe the structures and manufacturing methods described herein unless otherwise indicated. In a first aspect, the present invention provides a novel crystalline form of the irinotecan hydrochloride salt, in which the easiness of filtration is increased, which is called type I. Form I is characterized by powder X-ray diffraction ("PXRD") analysis and infrared diffuse reflectance analysis. PXRD and infrared diffuse reflectance patterns are provided as drawings (FIGS. 1 and 2, respectively).

Referring to Figure 1, the irinotecan hydrochloride type I PXRD is unique. Type I can be characterized by PXRD characteristics that are distinct from Types II, III, and IV shown in Table 1.

The test samples were ground and placed on a tray of a uniform X-ray apparatus (Scintag X ₂ Advance Diffraction) and tested at a wavelength of 1.540562 in the range of 5.00-40.00 (Deg.) At a continuous scan rate of 2.00 Deg / min.

Table 1

Peak position (2 θ ) burglar ( cps )

12.3406 1662.63

24.7913 913.23

10.9438 891.13

8.2056 762.43

27.6750 663.63

22.7206 648.02

21.2350 619.23

Referring to Figure 2, the infrared diffuse reflectance pattern of irinotecan hydrochloride type I shows the unique characteristics of type I.

We weighed about 3 mg of the sample, uniformly dispersed the sample in 300 mg of dry KBr, and then immediately recorded the spectrum in the range of 400 to 4000 cm ⁻¹ by diffuse reflectance. We performed a single test for each sample. The IR device is a Nicolet, Magna-IR 560 spectrometer. The number of sample scans is 32. The number of background scans is 32. The resolution is four. Sample acquisition is eight. The mirror speed is 0.6329. The effective aperture is 100.

Drying loss (LOD) of Form I was determined to be 7.9%. LOD was tested using TA instrument 2950.

Irinotecan hydrochloride Form I was prepared under the conditions described in Example 1. Other conditions under which irinotecan hydrochloride Form I are prepared can be found by general experiments.

Irinotecan hydrochloride Form I can be prepared by crystallizing irinotecan hydrochloride from a solution of ethanol, hydrochloric acid and N-heptane.

In a second aspect, the present invention provides another novel crystalline form of irinotecan hydrochloride, in which the easiness of filtration is increased, which is called type II. Type II has been characterized by PXRD analysis and infrared diffuse reflectance analysis. PXRD and infrared diffuse reflectance patterns are provided as figures (FIGS. 3 and 4, respectively).

Referring to Fig. 3, PXRD of irinotecan hydrochloride type II is unique. Type II can be characterized by PXRD characteristics that are distinct from Types I, III, and IV shown in Table 2.

The PXRD of FIG. 3 was performed using the same equipment and sample preparation used to describe the characteristics of Form I. Moreover, the test method used to measure PXRD, dry loss and infrared diffuse reflectance is the same for all crystalline forms of the irinotecan hydrochloride of the present invention.

Table 2

Peak position (2 θ ) burglar ( cps )

20.3956 746.23

22.2950 719.65

12.0744 428.83

8.4800 396.32

11.8306 381.37

15.7587 319.98

18.5200 301.87

Referring to FIG. 4, the infrared diffuse reflectance pattern of irinotecan hydrochloride type II shows the unique characteristics of type II.

Infrared diffuse reflectance of FIG. 4 was performed using the same equipment and sample preparation used to describe the characteristics of Form I.

Drying loss of type I was determined to be 7.8%.

Irinotecan hydrochloride Form II was prepared under the conditions described in Example 2. Other conditions under which irinotecan hydrochloride Form II are prepared can be found by general experiments.

Irinotecan hydrochloride Form II can be prepared by crystallizing irinotecan hydrochloride from a solution of ethanol and hydrochloric acid.

In a third aspect, the present invention provides another novel crystalline form of irinotecan hydrochloride with increased filtration ease, referred to as type III.

Form III is characterized by powder X-ray diffraction ("PXRD") analysis and infrared diffuse reflectance analysis. PXRD and infrared diffuse reflectance patterns are provided as figures (FIGS. 5 and 6, respectively).

Referring to Fig. 5, PXRD of irinotecan hydrochloride type III is unique. Type III can be characterized by the PXRD characteristics distinguished from Types I, II and IV shown in Table 3.

The PXRD of FIG. 5 was performed using the same equipment and sample preparation used to describe the features of Forms I and II.

TABLE 3

Peak position (2 θ ) burglar ( cps )

      23.9600 421.67

20.9200 365.00

21.0800 331.67

21.0944 308.53

23.8375 295.17

24.3200 236.67

10.2800 153.33

Referring to Figure 6, the infrared diffuse reflectance pattern of irinotecan hydrochloride type III shows the unique characteristics of type III.

The infrared diffuse reflectance pattern of FIG. 6 was performed using the same equipment and sample preparation used to describe the characteristics of Forms I and II.

Irinotecan hydrochloride Form III was prepared under the conditions described in Example 3. Other conditions under which irinotecan hydrochloride Form III are prepared can be found by general experiments.

Irinotecan hydrochloride Form III can be prepared by crystallizing irinotecan hydrochloride from a solution of methanol, ethyl acetate and hydrochloric acid.

In a fourth aspect, the present invention provides a novel crystalline form of irinotecan hydrochloride with increased filtration ease, which is called type IV. Form IV is characterized by powder X-ray diffraction ("PXRD") analysis and infrared diffuse reflectance analysis. PXRD and infrared diffuse reflectance patterns are provided as figures (FIGS. 7 and 8, respectively).

Referring to Fig. 7, PXRD of irinotecan hydrochloride IV type is unique. Type IV can be characterized by PXRD characteristics that are distinct from Types I, II, and III shown in Table 4.

The PXRD of FIG. 7 was performed using the same equipment and sample preparation used to describe the features of Forms I, II, and III.

Table 4

Peak position (2 θ ) burglar ( cps )

9.1912 1606.45

9.9800 1086.27

18.8937 766.67

15.2725 733.90

16.1681 709.22

25.7400 661.22

27.0662 539.37

Referring to FIG. 8, the infrared diffuse reflectance pattern of irinotecan hydrochloride Type IV exhibits a unique characteristic of Type IV.

The infrared diffuse reflectance pattern of FIG. 8 was performed using the same equipment and sample preparation that were used to describe the features of Types I, II, and III.

Irinotecan hydrochloride Form IV was prepared under the conditions described in Example 4. Other conditions under which irinotecan hydrochloride Form IV are prepared can be found by general experiments.

Irinotecan hydrochloride Form IV can be prepared by crystallizing irinotecan hydrochloride from a solution of ethanol, ethyl acetate and hydrochloric acid.

Irinotecan hydrochloride Forms I, II, III and IV are of use as active agents and dosage forms in pharmaceutical compositions for the treatment of metastatic carcinomas of the colon or rectum. Irinotecan hydrochloride Forms I, II, III and IV are also useful for preparing salts and solvates of irinotecan, such as the injection of irinotecan hydrochloride currently administered to patients in the United States. It is contemplated that such salts and solvates fall within the scope of the present invention to such an extent that the atomic position and molecular conformation of the irinotecan hydrochloride does not change significantly as the salt is formed or solvated.

Irinotecan hydrochlorides I, II, III and IV can be included in pharmaceutical products for administration to humans or other mammals in need of treating metastatic carcinoma of the colon or rectum. Pharmaceutical compositions and dosage forms can be formulated for transdermal administration.

Pharmaceutical compositions for transdermal administration contain excipients such as sorbitol NF powder and lactic acid. The pH of this solution can be adjusted to 3.5 (range from 3.0 to 3.8) using sodium hydroxide or hydrochloric acid. The composition is allowed to be diluted using 5% Dextrose Injection (USP (D5W)) or 0.9% Sodium Chloride Injection (USP) prior to intravenous infusion. Preferred diluent is 5% dextrose injection (USP).

The pharmaceutical compositions and dosage forms of the present invention may be administered in a manner that has previously been administered compositions containing irinotecan hydrochloride to a patient for the purpose of treating metastatic carcinoma of the colon or rectum. For this purpose, irinotecan hydrochloride Forms I, II, III and / or IV are preferably administered in an amount of about 75 to 180 mg / m 2.

While the present invention has been described above in connection with the preferred embodiment, the present invention will now be further described by the following examples. However, the present invention is not limited thereto.

In the drawings,

1 is a characteristic powder X-ray diffraction pattern of Form I.

Fig. 2 is an infrared diffuse reflectance pattern of type I.

3 is a characteristic powder X-ray diffraction pattern of Form II.

4 is an infrared diffuse reflectance pattern of type II.

5 is a characteristic powder X-ray diffraction pattern of type III.

Fig. 6 is an infrared diffuse reflectance pattern of type III.

7 is a characteristic powder X-ray diffraction pattern of type IV.

8 is an IV diffuse infrared reflectance pattern.

9 is a side-by-side comparison of the X-ray diffraction patterns of Types I to IV.

Preparation of Irinotegan Hydrochloride Type I

Example 1

A suitable container was filled with amorphous irinotecan acetate (6.35 g) and ethanol (45 mL). The resulting mixture was heated to reflux (about 70 ° C.) and maintained in suspension. 2N HCl (5.4 mL) was added to the reaction mixture to adjust the pH to 4 or less. N-heptane (25 mL) and ethanol (30 mL) were added to the resulting mixture. Subsequently, the solution was cooled to 0˜10 ° C., stirred at this temperature for 1 hour, and then 200 mL of ethyl acetate was poured into solvent exchange. This solution was then filtered and washed with ethyl acetate (50 mL). The solid was dried in vacuo. Since the water content was lower than expected, this solid was heated under high humidity for 1 hour, and then cooled to obtain irinotecan hydrochloride trihydrate Form I (6.6 g).

Preparation of Irinotegan Hydrochloride Type II

Example 2

A suitable container was filled with amorphous irinotecan acetate (14.5 g) and ethanol (101 mL). The resulting mixture was heated to reflux and maintained in suspension. 2N HCl (10 mL) was added to the reaction mixture to adjust the pH to 4 or less. Ethyl acetate (145 ml) was added to the resulting mixture. The mixture was then cooled to 0-10 [deg.] C., stirred at this temperature for 1 hour, filtered and washed with ethyl acetate (100 mL). The solid was then dried in vacuo. Since the water content was lower than expected, the solid was allowed to stand overnight in the atmosphere to obtain irinotecan hydrochloride trihydrate type II (13.5 g).

Preparation of Irinotecan Hydrochloride Type III

Example 3

100 mL of the reactor was charged with amorphous irinotecan acetate (2.0 g) and methanol (14 mL). This reaction mixture was heated to 50 ° C. 2N hydrochloric acid (6.2% by weight, about 1.7 mL) was added to adjust the pH to 4 or less to dissolve the solid particles. Ethyl acetate (40 mL) was slowly added to the mixture. This liquid mixture was cooled to 0-10 degreeC, and it stirred at this temperature for 1 hour. The solid particles were filtered off and washed with cold ethyl acetate (6 mL). The wet cake was dried in vacuo to yield 1.66 g of irinotecan hydrochloride trihydrate Form III.

Preparation of Irinotecan Hydrochloride Type IV

Example 4

16 L of reactor was charged with amorphous irinotecan acetate (234 g) and ethanol (1300 g). The reaction mixture was heated to reflux. 9N hydrochloric acid (14.3 wt.%, About 89 g) was added until the pH value of the solution was 4 or less to dissolve the solid particles. Ethyl acetate (2040 g) was slowly added to the mixture. This liquid mixture was cooled to 0-10 degreeC, and it stirred at this temperature for 1 hour. The solid particles were filtered off and washed with cold ethyl acetate (420 g). The wet cake was dried in vacuo to yield 160 g of irinotecan hydrochloride Form IV.

The present invention is not limited by the above-described embodiment given as embodiments, but may be modified in various ways within the scope of protection defined by the appended claims.

Provided are improved processing and preparation of pharmaceutical products containing novel crystalline forms of irinotecan hydrochloride. The new crystalline forms increase the possibilities available to scientists involved in the manufacture of pharmaceutical products, thereby producing new and improved pharmaceutical compositions that cannot be obtained by other methods, except for the present invention of the new crystalline forms. To make it possible.

Claims (20)

2 θ to Crystalline form of irinotecan hydrochloride characterized by a powder X-ray diffraction pattern with peaks at 20.3956 ± 0.2 °, 22.2950 ± 0.2 °, 12.0744 ± 0.2 °, 8.4800 ± 0.2 ° and 11.8306 ± 0.2 °. According to claim 1, 2 θ ± 0.2 ° 15.7587 and 18.5200 ± 0.2 ° in the crystal form of irinotecan hydrochloride characterized by a powder X-ray diffraction pattern with a peak to. The crystalline form of irinotecan hydrochloride according to claim 1, characterized by an infrared diffuse reflectance pattern having peaks at 1749 ± 0.5, 1189 ± 0.5, 1234 ± 0.5, 1663 ± 0.5, and 1720 ± 0.5 waves. The method of claim 1 wherein the crystalline form of irinotecan hydrochloride, characterized in the powder X-ray diffraction pattern is that with a peak such as shown in the following Table 2 as θ.

The crystalline form of irinotecan hydrochloride according to claim 1, characterized by an infrared diffuse reflectance pattern having a peak as shown in the following table.

a) dissolving irinotecan in ethanol and hydrochloric acid, b) crystallizing irinotecan hydrochloride from ethanol and hydrochloric acid to produce the crystalline form of claim 1, c) separating the crystalline form of the irinotecan hydrochloride from ethanol and hydrochloric acid Method for producing the irinotecan hydrochloride crystal form of claim 1 comprising a. 2 θ ± 0.2 ° to 23.9600, 20.9200 and 21.0800 ± 0.2 ° ± 0.2 ° in the crystal form of irinotecan hydrochloride, which is characterized by powder X-ray diffraction pattern with a peak. The method of claim 7, 2 θ 21.0944 ± 0.2 °, 23.8375 ± 0.2 °, 24.3200 ± 0.2 ° , and 10.2800 ± 0.2 ° in the crystal form of irinotecan hydrochloride characterized by a powder X-ray diffraction pattern with a peak to. 8. The crystalline form of irinotecan hydrochloride according to claim 7, characterized by an infrared diffuse reflectance pattern with peaks at waves of 1229 ± 0.5, 1721 ± 0.5, 1190 ± 0.5, 1659 ± 0.5 and 1598 ± 0.5. The method of claim 7, wherein the crystalline form of irinotecan hydrochloride characterized by the X-ray diffraction pattern having a peak like that shown in the following table 2 as θ.

8. The crystalline form of irinotecan hydrochloride according to claim 7, characterized by an infrared diffuse reflectance pattern having a peak as shown in the table below.

a) dissolving irinotecan in methanol, ethyl acetate and hydrochloric acid, b) crystallizing the irinotecan hydrochloride from methanol, ethyl acetate and hydrochloric acid to produce the crystalline form of claim 7, c) separating the crystalline form of the irinotecan hydrochloride from methanol, ethyl acetate and hydrochloric acid Method for producing the irinotecan hydrochloride crystal form of claim 7 comprising a. a) dissolving irinotecan in ethanol, N-heptane and hydrochloric acid, b) crystallizing irinotecan hydrochloride from ethanol, N-heptane and hydrochloric acid to produce a crystalline form, c) separating the crystalline form of the irinotecan hydrochloride from ethanol, N-heptane and hydrochloric acid Including, The crystalline form of the irinotecan hydrochloride is 2 θ with powder X-ray with peaks at 12.3406 ± 0.2 °, 24.7913 ± 0.2 °, 10.9438 ± 0.2 °, 8.2056 ± 0.2 °, 27.6750 ± 0.2 °, 22.7206 ± 0.2 ° and 21.2350 ± 0.2 ° A method for producing an irinotecan hydrochloride crystalline form, characterized by a diffraction pattern. The method of claim 13, wherein the crystalline form of irinotecan hydrochloride is characterized by an infrared diffuse reflectance pattern with peaks at 1686 ± 0.5, 1612 ± 0.5, 1748 ± 0.5, 1192 ± 0.5, and 1663 ± 0.5 wavenumbers. 14. The method of claim 13, wherein the crystal form of the irinotecan hydrochloride is characterized by the X-ray diffraction pattern with a peak such as shown in the following Table 2 as θ.

The method of claim 13, wherein the crystalline form of the irinotecan hydrochloride is characterized by an infrared diffuse reflectance pattern having peaks as shown in the table below.

a) dissolving irinotecan in ethanol, ethyl acetate and hydrochloric acid, b) crystallizing the irinotecan hydrochloride from ethanol, ethyl acetate and hydrochloric acid to form a crystalline form; c) separating the crystalline form of the irinotecan hydrochloride from ethanol, ethyl acetate and hydrochloric acid Including, The crystalline form of the irinotecan hydrochloride is 2 θ with a powder X-ray with peaks at 9.1912 ± 0.2 °, 9.9800 ± 0.2 °, 18.8937 ± 0.2 °, 15.2725 ± 0.2 °, 16.1681 ± 0.2 °, 25.7400 ± 0.2 ° and 27.0662 ± 0.2 ° A method for producing an irinotecan hydrochloride crystalline form, characterized by a diffraction pattern. 18. The method of claim 17, wherein the crystalline form of irinotecan hydrochloride is characterized by an infrared diffuse reflectance pattern with peaks at frequencies of 1712 ± 0.5, 1231 ± 0.5, 1188 ± 0.5, 1668 ± 0.5, and 1432 ± 0.5. 18. The method of claim 17, wherein the crystal form of the irinotecan hydrochloride is characterized by the X-ray diffraction pattern with a peak such as shown in the following Table 2 as θ.

18. The method of claim 17, wherein the crystalline form of the irinotecan hydrochloride is characterized by an infrared diffuse reflectance pattern having peaks as shown in the table below.

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